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US9487574B2 - Antigen specific multi epitope vaccines - Google Patents

Antigen specific multi epitope vaccines Download PDF

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US9487574B2
US9487574B2 US12/442,495 US44249507A US9487574B2 US 9487574 B2 US9487574 B2 US 9487574B2 US 44249507 A US44249507 A US 44249507A US 9487574 B2 US9487574 B2 US 9487574B2
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peptide
cancer
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cell
epitopes
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US20100074925A1 (en
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Lior Carmon
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VAXIL BIOTHERAPEUTICS Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/19—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4256—Tumor associated carbohydrates
    • A61K40/4257—Mucins, e.g. MUC-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4727—Mucins, e.g. human intestinal mucin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to cancer peptide vaccines with pan HLA class I and class II binding properties, as well as to pharmaceutical compositions containing the peptide vaccines and methods for treating or preventing cancer.
  • therapeutic vaccines such as anti-cancer vaccines and prophylactic (preventive or “conventional”) anti-infective vaccines.
  • therapeutic vaccines are generally expected to treat sick individuals, suggesting that a broader and stronger immune response is required.
  • prophylactic vaccines are generally induced against highly immunogenic “foreign” epitopes derived from viruses or bacteria and thus easily induce a strong response with a high number of T cell specific clones.
  • therapeutic vaccines in particular cancer vaccines composed of self derived TAAs are less immunogenic and therefore are frequently associated with low or minimal induction of activated T cell clones.
  • a desired therapeutic vaccine would need to prime a robust cellular reaction, which will involve multiple clones of T cell lymphocytes predominantly T killer (CD8 + ) and T Helper (CD4 + ).
  • MHC class I-restricted TAA peptides are the targets of Cytotoxic T lymphocytes (CTL), which constitute one of the powerful effectors of the immune system against tumors (Townsend et al., 1989).
  • CTL Cytotoxic T lymphocytes
  • These peptide vaccines are usually 8 to 10 amino acids (AA) long, with 2 to 3 primary anchor residues that interact with the Major Histocompatibility complex (MHC) class I molecules and 2 to 3 AA residues that engage the T-cell receptor on CD8 + cells (Rammensee et al., 1993).
  • MHC Major Histocompatibility complex
  • CD8 + epitopes subsequent to the search for MHC-binding motifs in known putative TAAs, (Kast et al., 1994) as was shown in the case of the breast-carcinoma-associated HER-2/neu receptor (Fisk et al., 1995) or the colorectal tumor associated Carcino-Embryonic Antigen (CEA) (Ras et al., 1997).
  • CD4 + T-cell responses are essential to promote the accumulation of Antigen-Presenting Cells (APC) for effective immune priming (Hung et al. 1998) and also for extending the life of anti-tumor CD8 + T cells i.e. memory response vs. short living response.
  • APC Antigen-Presenting Cells
  • MHC class I epitopes led in many cases to the administration of MHC class I epitopes with universal non-specific MHC class II restricted epitopes such as the pan-class II epitope peptide PADRE (Weber et al., 1999). Although response against the universal MHC class II-restricted epitopes was increased, elevation in CD8 + T-cell effectors specific to the MHC class I-restricted epitope have been limited (Weber et al., 1999).
  • CD4 + T cells Another important feature of CD4 + T cells is their role as effector cells with direct anti-tumor activity (Pardoll and Topalian 1998, Christopher et al., 2000).
  • MHC class II peptide ligands do not have restricted binding properties, their isolation is more complicated.
  • successful attempts in this direction were limited and arrived only more recently along with the development of sophisticated in-silico class II prediction software and class II transgenic mice (Chaux et al., 1999; Manici et al., 1999). Nevertheless, selected publications e.g.
  • the other strategy used to overcome the limited repertoire of anti-tumor CD8 + T cell clones is the use of the entire TAA rather then selecting and defining the only relevant immunodominant epitopes.
  • This strategy is more straightforward, as one does not need to isolate the immunogenic epitopes within a given TAA. However, it may very well lead to the “dilution” of the immunogenic epitopes with less immunogenic epitopes, hence decreasing the level of specific immunity or reduce the repertoire of anti-tumor CD8 + T cell clones. Furthermore, some of these less immunogenic epitopes could potentially induce a status of “Immune Anergy” (non responsiveness) which can potentially lead to a decrease in the intensity of the specific immunity or even to status of autoimmunity.
  • the peptide-specific T cells were able to lyse tumors. More importantly, the responses lasted for a long time and were detectable for more than a year after the final vaccination in select patients. This study suggested an improved anti-cancer immunity via combination of class-I and class-II epitopes derived from the same TAA.
  • cancer therapeutic vaccines are required to be:
  • SP signal peptides
  • Signal peptides generally consist of three parts: an N-terminal region of differing length, which usually comprises positively charged amino acids; a hydrophobic domain; and a short carboxy-terminal peptide segment.
  • pre-protein a nascent precursor protein
  • ER Endoplasmic Reticulum
  • the signal peptide directs the pre-protein to the cytoplasmic membrane.
  • the signal peptide is not responsible for the final destination of the mature protein; secretory proteins devoid of further address tags in their sequence are by default secreted to the external environment.
  • Signal peptides are cleaved from precursor proteins by an endoplasmic reticulum (ER)-resident signal peptidase or they remain uncleaved and function as a membrane anchor.
  • ER endoplasmic reticulum
  • Signal peptides are cleaved from precursor proteins by an endoplasmic reticulum (ER)-resident signal peptidase or they remain uncleaved and function as a membrane anchor.
  • ER endoplasmic reticulum
  • the signal peptide enhances the ability of the epitope to attract and activate CD8+ T cells (Minev B R, et al, 2000).
  • TAA Transporter for Antigen Presentation
  • the signal peptide merely acts as a chaperon or tag for selected epitopes/Vaccines.
  • These vaccines suffer from several drawbacks as they utilize selected immunogenic epitopes, MHC-class I-restricted peptides with limited repertoire for activation, or non-defined immunogenic epitopes with non-specific activity.
  • MUC1 is one of the most promising TAAs known today.
  • This polymorphic epithelial mucin, encoded by the MUC1 gene is a high-molecular-weight glycoprotein with few alternative-splicing variants encoding for both a transmembranal (i.e. across the cell membrane) and a secreted (i.e. circulating) product both expressed in a broad range of tumors (Graham et al., 1996; Ho et al., 1993).
  • MUC1 is one of the few known targets that are expressed by more than 90 percent of common solid tumor cancers including Colon, Gastric, Lung, Renal Cell (RC), Transitional Cell (TC), Prostate, Pancreas, Breast, Ovary and Thyroid.
  • MUC1 Lymphoma, Leukemia, and Multiple Myeloma
  • Treon and his colleagues also determined elevation in soluble MUC1 levels in MM patients using an immunoassay that recognizes the CA27.29 MUC1 epitope. He further demonstrate that MUC1 levels are elevated in both bone marrow (BM) and peripheral blood plasma of MM patients in comparison to healthy donors, and that BM MUC1 levels are associated with tumor burden in MM patients.
  • BM bone marrow
  • MUC1 extracellular tandem repeat array
  • MAbs monoclonal antibodies
  • CTLs MHC-restricted CD8 + T cells
  • BAGE Another example of a tumor associated antigen is BAGE.
  • BAGE codes for a putative protein of 43 amino acids and seems to belong to a family of several genes.
  • Gene BAGE is expressed in 22% of melanomas, 30% of infiltrating bladder carcinomas, 10% of mammary carcinomas, 8% of head and neck squamous cell carcinomas, and 6% of non-small cell lung carcinomas. It is silent in normal tissues with the exception of testis (Boel et al., 1995).
  • ARMET Arginine rich, mutated in early stage of tumors
  • ARP Arginine-rich protein
  • ARP Arginine-rich protein
  • the present invention relates to promiscuous peptide vaccines comprising multiple MHC class I, and MHC class II epitopes of a given protein antigen. More particularly, the present invention relates to promiscuous peptide vaccines comprising multiple MHC class I and MHC class II epitopes with the specificity of a given antigen derived from the entire signal peptide domain of that protein antigen. These MHC class I and MHC class II epitopes have a high frequency in the population and thus the vaccine is effective in a large portion of the population.
  • the present invention thus provides a peptide vaccine which is able to induce strong, comprehensive response in the majority of the target population against said antigen. More specifically, but without wishing to be limited to a single hypothesis, such a vaccine preferably combines activation of both CD4 + and CD8 + T cells via multiple CD4 + and CD8 + -restricted epitopes which are present within the internal sequences of the vaccine and are derived from the same antigen.
  • the present invention relates to such peptide vaccines comprising the signal peptide domain of tumor associated antigens (TAA) or the signal peptide domain of proteins which are over-expressed in tumor cells.
  • TAA tumor associated antigens
  • the present invention relates to peptide vaccines comprising the signal peptide of a protein which is either a TAA or is over-expressed in tumor cells, wherein said peptides are recognized and presented by more than 50% of the MHC class I and MHC Class II alleles in the population.
  • said peptide is not longer than 50 amino acids, more preferably, not longer than 25 amino acids.
  • the peptide vaccines of the invention comprise the signal peptide of proteins selected from the group consisting of Armet, HSP60, CANX, MTHFD2, FAP, MMP6, BAGE-1, GNTV, Q5H943, MUC1, CEA, Pmel, Kallikrein-4, Mammaglobin-1, MART-1, GPR143-OA1, PSA, TRP1, Tyrosinase, FGF-5, NEU proto-oncogene, Aft, MMP-2, PSMA, Telomerase-associated protein 2, PAP, Uroplakin II and Proteinase 3, i.e. SEQ ID Nos. 1-28, respectively (Table 1).
  • the present invention relates to tumor associated antigen peptides comprising the signal peptide domain of the polymorphic epithelial mucin, encoded by the MUC1 gene.
  • the present invention thus provides a promiscuous peptide vaccine comprising the MUC1 signal peptide domain which is able to induce strong, comprehensive response in the majority of the target population against any MUC1 positive tumor.
  • the MUC1 signal peptide-derived peptide vaccines are able to bind to the majority of MHC Class I alleles in the population and thus induce CD8+ T-cell mediated cell lysis, and are also able to bind to bind to the majority of MHC Class II alleles in the population and thus prime an effective CD4+ T-cell mediated immune response.
  • the MUC1 signal peptide-derived peptide vaccine comprises the amino acid sequence MTPGTQSPFFLLLLLTVLTVV (SEQ ID NO. 10).
  • the peptide vaccine of the invention comprises a mixture of at least two short peptides of preferably about nine amino acid residues in length derived from the signal peptide domain of the MUC1 protein.
  • These peptides represent various MHC Class I and Class II epitopes which are included in the MUC1 signal peptide. Their combination results in effective binding of the vaccine composition to various alleles of MHC class I and MHC class II molecules, and thus to the induction of an immune response to tumors expressing the MUC1 protein.
  • This response may include inducing “help” for priming a strong T cell activity via CD4+ T cell activation, combined with induction of CD8+ T cell activation, and potent cellular activity (CTL) against MUC1 expressing tumors.
  • CTL potent cellular activity
  • the mixture of short peptides comprises at least two peptides selected from the group consisting of SEQ ID NO: 29-39.
  • the mixture of short peptides comprises VXL01 (SEQ ID NO 29), VXL02 (SEQ ID NO 30), VXL04 (SEQ ID NO 31) and VXL05 (SEQ ID NO 32).
  • the present invention relates to peptide vaccines derived from the signal peptide domain of the BAGE-1 gene.
  • the BAGE-1 signal peptide-derived peptide vaccine comprises the amino acid sequence MAARAVFLAL SAQLLQA (SEQ ID NO. 7).
  • the present invention relates to peptide vaccines derived from the signal peptide domain of the Armet gene.
  • the Armet signal peptide-derived peptide vaccine comprises the amino acid sequence MWATQGLAVA LALSVLPGSR A (SEQ ID NO. 1).
  • the present invention also concerns use of the peptide vaccines described above in the preparation of pharmaceutical compositions for treating or inhibiting cancer.
  • the invention further concerns pharmaceutical compositions comprising said peptide vaccines and the use of said peptide vaccines or said pharmaceutical compositions as anti-tumor vaccines to treat or inhibit the development of cancer.
  • pharmaceutical compositions comprising said peptide vaccines and the use of said peptide vaccines or said pharmaceutical compositions as anti-tumor vaccines to treat or inhibit the development of cancer.
  • tumors which over-expresses the protein from which the signal peptide vaccine was derived, for example, MUC1-expressing cancer, BAGE-1-expressing cancer, or Armet-expressing cancer.
  • the invention further concerns nucleic acid molecules encoding said peptides, and antigen presenting cells (APC), e.g. dendritic cells, presenting said peptides, as well as pharmaceutical compositions comprising said nucleic acid molecules, or said cells.
  • APC antigen presenting cells
  • the invention also concerns use of the peptide vaccines for enrichment of T cell populations in vitro. Thus obtaining a peptide-specific enriched T cell population.
  • the invention further concerns the use of said nucleic acid molecules, cells, or pharmaceutical compositions comprising same as anti-tumor vaccines to treat or inhibit the development of cancer.
  • tumors which over-expresses the protein from which the signal peptide vaccine was derived, for example, MUC1-expressing cancer, BAGE-1-expressing cancer, or Armet-expressing cancer.
  • Further aspects of the present invention are directed to a method for treating or for inhibiting the development of cancer by administering the pharmaceutical compositions of the present invention to a patient in need thereof.
  • compositions of the invention may be adapted for use in combination with other anti neoplastic agents.
  • FIG. 1 is a graph showing results of an ELISA quantitative assay measuring cytokine secretion profiles of a specific T cell subpopulation developed via repeated stimulation with ImMucin. The results represent one out of two experiments using four different donors.
  • FIG. 2 is a graph showing FACS analysis of T cell phenotype evaluation during consistent stimulation with ImMucin. The Results represent one out of two experiments using four different donors.
  • the present invention provides antigen specific vaccines which are capable of inducing a robust T-cell immunity and which are applicable to the majority of the population.
  • SP signal peptides
  • the present invention is based on the surprising finding that SP-derived vaccines are able to bind simultaneously to multiple alleles of both MHC class I and MHC class II i.e. CD4 + and CD8 + -restricted epitopes.
  • a signal peptide vaccine although containing just one sequence, could thus be compared to a large number of single Class I and Class II epitopes, used in a mixture.
  • This newly discovered feature of SP-vaccines facilitates the generation of a robust immune response in the majority of the target population.
  • signal peptide-based vaccines bare the ability to independently penetrate the ER and thus, at least partially, avoid immune escape mechanisms such as TAP deficiency.
  • the objective of the predictive algorithm is to identify and obtain signal peptide (SP) targets with a potential role as cancer vaccines.
  • SP signal peptide
  • Proteins with the following attributes are removed from the list of putative targets as being non eligible for an immune assault:
  • Proteins that are found to be eligible targets for an immune assault are next examined for the presence of a signal peptide. This may be done by using appropriate computer software, e.g. the Signal P 3.0.
  • the Signal P 3.0 program uses both a neural network (NN) algorithm and a Hidden Markov models (HMM) algorithm for selection of the signal.
  • N neural network
  • HMM Hidden Markov models
  • a sequence was considered to be a signal peptide whenever a score of over 0.2 was received in one or more of the algorithms. Sequences having a score of above 0.7 are preferred. Sequences having a score of above 0.8 are most preferred.
  • cancer protein targets eligible for an immune assault and having an identified signal peptide sequence of 17-50 amino acids are selected for further examination of predicted binding to MHC alleles.
  • a prediction of putative binding of the selected candidate signal peptide sequences to frequently occurring HLA haplotypes is made based on information concerning HLA allele frequency (class I and II) which may be obtained, for example, from the dbMHC site belonging to the NCBI.
  • HLA-A, B, C HLA class I
  • HLA-DRB1 HLA class II
  • HLA-A, B, C HLA class II
  • HLA-DRB1 HLA class II
  • DR-B1 Allele quency Allele quency Allele Frequency HLA-A24 0.36
  • DR-B1 1501 0.13 DR-B1 04 0.31 HLA-A0201 0.27
  • DR-B1 1101 0.13 DR-B1 11 0.17 HLA-A01 0.12
  • the binding strength of the previously identified signal peptides to the HLA alleles is predicted using any of numerous available software programs.
  • the following is a non-limiting list of available prediction programs:
  • the probability that the patient has one or more of the binding alleles is 1 minus the probability that he would have none of the binding alleles:
  • the most suitable SP vaccine candidates are chosen according to the following criteria:
  • a MUC1 SP vaccine (hereinafter termed “VXL100” or “ImMucin”) was prepared.
  • the ImMucin vaccine of the invention is composed of a 21 amino acid (AA)-long peptide derived from the signal peptide domain of the MUC1 protein and comprises the amino acid sequence MTPGTQSPFFLLLLLTVLTVV (SEQ ID NO 10).
  • This peptide vaccine is processed in the antigen-presenting cell (APC) and presented to immune effector cells by MHC class I, and II molecules.
  • APC antigen-presenting cell
  • the present invention concerns a vaccine comprising a mixture of short peptides comprising MHC Class I and II epitopes within the MUC1 signal domain.
  • short peptides include:
  • TAA tumor associated antigen
  • SEQ ID NO 29 LLLTVLTVV (designated VXL01)
  • SEQ ID NO 30 LLLLTVLTV (designated VXL02)
  • SEQ ID NO 31 TQSPFFLLL (designated VXL04)
  • SEQ ID NO 32 SPFFLLLLL (designated VXL05)
  • SEQ ID NO 33 FLLLLLTVL
  • SEQ ID NO 34 LLLLLTVLT
  • GTQSPFFLL GTQSPFFLL
  • TPGTQSPFF SEQ ID NO 37 FFLLLLLTV
  • SEQ ID NO 38 MTPGTQSPF SEQ ID NO 39: QSPFFLLLL
  • TAA tumor associated antigen
  • peptide refers to a molecular chain of amino acids, which, if required, can be modified in vivo or in vitro, for example by manosylation, glycosylation, amidation (specifically C-terminal amides), carboxylation or phosphorylation with the stipulation that these modifications must preserve the biological activity of the original molecule.
  • peptides can be part of a chimeric protein.
  • Functional derivatives of the peptides are also included in the present invention.
  • Functional derivatives are meant to include peptides which differ in one or more amino acids in the overall sequence, which have deletions, substitutions, inversions or additions.
  • Amino acid substitutions which can be expected not to essentially alter biological and immunological activities have been described.
  • Amino acid replacements between related amino acids or replacements which have occurred frequently in evolution are, inter alia Ser/Ala, Ser/Gly, Asp/Gly, Asp/Asn, Ile/Val see Dayhof M. D (1978). Based on this information, Lipman and Pearson (1985) developed a method for rapid and sensitive protein comparison and determining the functional similarity between homologous polypeptides.
  • the peptides according to the invention can be produced synthetically, by recombinant DNA technology. Methods for producing synthetic peptides are well known in the art.
  • the organic chemical methods for peptide synthesis are considered to include the coupling of the required amino acids by means of a condensation reaction, either in homogenous phase or with the aid of a so-called solid phase.
  • the condensation reaction can be carried out as follows:
  • Activation of the carboxyl group can take place, inter alia, by converting the carboxyl group to an acid halide, azide, anhydride, imidazolide or an activated ester, such as the N-hydroxy-succinimide, N-hydroxy-benzotriazole or p-nitrophenyl ester.
  • polypeptide to be expressed is coded for by a nucleic acid sequence.
  • nucleic acid sequence comprising the sequence encoding the peptides according to the present invention.
  • the degeneracy of the genetic code permits substitution of bases in a codon to result in another codon still coding for the same amino acid, e.g., the codon for the amino acid glutamic acid is both GAT and GAA. Consequently, it is clear that for the expression of a polypeptide with an amino acid sequence as shown in any of SEQ ID NO: 1-28 use can be made of a derivate nucleic acid sequence with such an alternative codon composition thereby different nucleic acid sequences can be used.
  • Nucleotide sequence refers to a polymeric form of nucleotides of any length, both to ribonucleic acid (RNA) sequences and to deoxyribonucleic acid (DNA) sequences. In principle, this term refers to the primary structure of the molecule. Thus, this term includes double and single stranded DNA, as well as double and single stranded RNA, and modifications thereof.
  • nucleotide sequences encoding the peptide vaccines of the invention can be used for the production of the peptides using recombinant DNA techniques.
  • the nucleotide sequence must be comprised in a cloning vehicle which can be used to transform or transfect a suitable host cell.
  • useful cloning vehicles may include chromosomal, non-chromosomal and synthetic DNA sequences such as various known bacterial plasmids, and wider host range plasmids such as pBR 322, the various pUC, pGEM and pBluescript plasmids, bacteriophages, e.g. lambda-gt-Wes, Charon 28 and the M13 derived phages and vectors derived from combinations of plasmids and phage or virus DNA, such as SV40, adenovirus or polyoma virus DNA.
  • chromosomal, non-chromosomal and synthetic DNA sequences such as various known bacterial plasmids, and wider host range plasmids such as pBR 322, the various pUC, pGEM and pBluescript plasmids, bacteriophages, e.g. lambda-gt-Wes, Charon 28 and the M13 derived phages and vectors
  • Useful hosts may include bacterial hosts, yeasts and other fungi, plant or animal hosts, such as Chinese Hamster Ovary (CHO) cells, melanoma cells, dendritic cells, monkey cells and other hosts.
  • bacterial hosts such as Chinese Hamster Ovary (CHO) cells, melanoma cells, dendritic cells, monkey cells and other hosts.
  • yeasts and other fungi such as Chinese Hamster Ovary (CHO) cells, melanoma cells, dendritic cells, monkey cells and other hosts.
  • CHO Chinese Hamster Ovary
  • Vehicles for use in expression of the peptides may further comprise control sequences operably linked to the nucleic acid sequence coding for the peptide.
  • control sequences generally comprise a promoter sequence and sequences which regulate and/or enhance expression levels.
  • an origin of replication and/or a dominant selection marker are often present in such vehicles.
  • control and other sequences can vary depending on the host cell selected.
  • the present invention also provides a polynucleotide encoding the signal peptide vaccine of the invention as part of a pharmaceutical composition preferably for targeted treatment of a tumor.
  • Further aspects of the present invention are directed to a method for treating or for inhibiting the development of cancer by administering the pharmaceutical compositions of the present invention to a patient in need thereof.
  • the present invention describes a method for treating or inhibiting the development of solid tumors for example, Colon, Gastric, Lung, Renal Cell (RC), Transitional Cell (TC), Prostate, Pancreas, Breast, Ovary or Thyroid cancers, as well as non-solid tumors such as Lymphoma, Leukemia, and Multiple Myeloma.
  • solid tumors for example, Colon, Gastric, Lung, Renal Cell (RC), Transitional Cell (TC), Prostate, Pancreas, Breast, Ovary or Thyroid cancers, as well as non-solid tumors such as Lymphoma, Leukemia, and Multiple Myeloma.
  • the present invention provides a method for treating or for inhibiting the development of MUC1-expressing cancers by administering the MUC1 signal peptide-derived peptide vaccine of the present invention to a patient in need thereof.
  • the present invention provides a method for treating or for inhibiting the development of BAGE1-expressing cancers by administering the BAGE1 signal peptide-derived peptide vaccine of the present invention to a patient in need thereof.
  • cancers include melanoma, bladder carcinoma, mammary carcinoma, head and neck squamous cell carcinoma, and non-small cell lung carcinomas.
  • the present provides a method for treating or for inhibiting the development of Armet-expressing cancers by administering the Armet signal peptide-derived peptide vaccine of the present invention to a patient in need thereof.
  • Such cancers include renal cell carcinomas, lung, breast, prostate, squamous cell carcinoma, head and neck carcinoma, pancreatic carcinoma.
  • the peptide vaccine of the invention is administered in an immunogenically effective amount with or without a co-stimulatory molecule.
  • the peptide vaccine may be administrated to a subject in need of such treatment for a time and under condition sufficient to prevent, and/or ameliorate the condition of cancer being treated.
  • the antigen and co-stimulatory molecule are formulated, separately or as a “chimeric vaccine” formulation, with a pharmaceutically acceptable carrier and administered in an amount sufficient to elicit a T lymphocyte-mediated immune response.
  • the peptide may be administered to subjects by a variety of administration modes, including by intradermal, intramuscular, subcutaneous, intravenous, intra-atrial, intra-articular, intraperitoneal, parenteral, oral, rectal, intranasal, intrapulmonary, and transdermal delivery, or topically to the eyes, ears, skin or mucous membranes.
  • the antigen may be administered ex-vivo by direct exposure to cells, tissues or organs originating from a subject (Autologus) or other subject (Allogeneic), optionally in a biologically suitable, liquid or solid carrier.
  • the peptides or pharmaceutical composition with or without a co-stimulatory molecule are delivered to a common or adjacent target site in the subject, for example to a specific target tissue or cell population in which the vaccine formulation is intended to elicit an immune response.
  • the peptide or pharmaceutical composition and the optional co-stimulatory molecule are administered separately, they are delivered to the same or closely proximate site(s), for example to a single target tissue or to adjacent sites that are structurally or fluidly connected with one another (e.g., to allow direct exposure of the same cells, e.g., fluid flow transfer, dissipation or diffusion through a fluid or extracellular matrix of both vaccine agents).
  • a shared target site for delivery of antigen and co-stimulatory molecule can be a common surface (e.g., a mucosal, basal or lunenal surface) of a particular target tissue or cell population, or an extracellular space, lumen, cavity, or structure that borders, surrounds or infiltrates the target tissue or cell population.
  • a common surface e.g., a mucosal, basal or lunenal surface
  • the peptide antigen with or without a co-stimulatory molecule may be administered to the subject separately or together, in a single bolus delivery, via continuous delivery (e.g., continuous intravenous or transdermal delivery) over an extended time period, or in a repeated administration protocol (e.g., on an hourly, daily or weekly basis).
  • continuous delivery e.g., continuous intravenous or transdermal delivery
  • a repeated administration protocol e.g., on an hourly, daily or weekly basis.
  • the various dosages and delivery protocols contemplated for administration of peptide and co-stimulatory molecule, in simultaneous or sequential combination are immunogenically effective to inhibit the occurrence or alleviate one or more symptoms of the target cancer in the subject.
  • an “immunogenically effective amount” of the antigen thus refers to an amount that is, in combination, effective, at dosages and for periods of time necessary, to elicit a specific T lymphocyte mediated immune response.
  • This response can be determined by conventional assays for T-cell activation, including but not limited to assays to detect proliferation, specific cytokine activation and/or cytolytic activity.
  • the amount of peptide vaccine is immunogenically effective to achieve a desired cancer inhibitory effect in the subject.
  • an immunogenically effective amount of the peptide depending on the selected mode, frequency and duration of administration, will effectively prevent cancer, or will inhibit progression of a cancerous condition in the subject.
  • an immunogenically effective dosage of the antigen which may include repeated doses within an ongoing prophylaxis or treatment regimen, will alleviate one or more symptoms or detectable conditions associated with a cancerous disorder. This includes any detectable symptom or condition amenable to prophylaxis and/or treatment with the vaccines of the invention, for example symptoms or conditions associated with breast cancer, cervical cancer, prostate cancer, colon cancer, melanoma and other cancerous conditions.
  • peptide antigens might be formulated with a “pharmaceutical acceptable carrier”.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption enhancing or delaying agents, and other excipients or additives that are physiologically compatible.
  • the carrier is suitable for intranasal, intravenous, intramuscular, intradermal, subcutaneous, parenteral, oral, transmucosal or transdermal administration.
  • the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound.
  • Peptide vaccine may be administered to the subject in the form of a peptide solution per se or a combination of a peptide with an appropriate auxiliary agent using an injector.
  • the peptide vaccine may be percutaneously administered through mucous membrane by, for instance, spraying the solution.
  • the unit dose of the peptide typically ranges from about 0.01 mg to 100 mg, more typically between about 100 micrograms to about 5 mg, which may be administered, one time or repeatedly, to a patient.
  • auxiliary agents which can be formulated with or conjugated to peptide or protein antigens and/or vectors for expressing co-stimulatory molecules to enhance their immunogenicity for use within the invention include cytokines (e.g. GM-CSF), bacterial cell components such as BCG bacterial cell components, imnunostimulating complex (ISCOM), extracted from the tree bark called QuillA (Morein et al., 1984 incorporated herein by reference), QS-21, a saponin-type auxiliary agent (Wu et al., (1992), incorporated herein by reference), Montanide ISA 51VG, liposomes, aluminum hydroxide (alum), bovine serum albumin (BSA), tetanus toxoid (TT) (Green et al., (1982) incorporated herein by reference) and keyhole limpet hemocyanin (KLH).
  • cytokines e.g. GM-CSF
  • bacterial cell components such as BCG bacterial cell components
  • compositions of the present invention it may be desirable to modify the peptide antigen, or to combine or conjugate the peptide with other agents, to alter pharmacokinetics and biodistribution.
  • a number of methods for altering pharmacokinetics and biodistribution are known to persons of ordinary skill in the art. Examples of such methods include protection of the proteins, protein complexes and polynucleotides in vesicles composed of other proteins, lipids (for example, liposomes), carbohydrates, or synthetic polymers.
  • the vaccine agents of the invention can be incorporated into liposomes in order to enhance pharmacokinetics and biodistribution characteristics.
  • liposome delivery vehicles peptides are typically entrapped within the liposome, or lipid vesicle, or are bound to the outside of the vesicle.
  • peptide antigens are associated with liposomes, such as lecithin liposomes or other liposomes known in the art, as a DNA-liposome mixture, or the DNA may be associated with an adjuvant known in the art to boost immune responses, such as a protein or other carrier.
  • Additional agents which assist in the cellular uptake of DNA such as, but not limited to, calcium ions, viral proteins and other transfection facilitating agents and methods may also be used to advantage (Wigler et al., Cell 14:725, 1978; Corsaro and Pearson, Somatic Cell Genetics 7:603, 1981; Graham and Van der Eb, Virology 52:456, 1973; Neumann et al., EMBO J. 1:841-845, 1982; and Hawley-Nelson et al., Focus 15:73-79, 1993, each incorporated herein by reference).
  • Human PBMC were separated from buffy coat samples of naive donors using Ficoll UNI-SEPmaxi tube. Separated cells were suspended in RPMI medium supplemented with 10% FCS, L-Glutamine, Sodium Pyruvate, MEM-EAGLE non-essential amino-acids, HEPES and Gentamycin Sulphate (Bet-Haemek Industries, IL) and cultivated for 4 h at 37° C.
  • Adherent cells were collected and cultured for 7 days in serum free DCCM-1 medium supplemented with L-Glutamine, huIL-4 (1000 IU/ml) (Cytolab IL) and GM-CSF-80 ug/ml (Cytolab IL). On day seven floating cells were collected and loaded with 50 ug/ml of examined peptide for 18 h at 37° C.
  • T cell medium contained RPMI medium supplemented with 10% FCS, L-Glutamine, Sodium Pyruvate, MEM-EAGLE non-essential amino-acids, HEPES and Gentamycin Sulphate (Bet-Haemek Industries, IL) as well as with 501 U/ml of recombinant IL-7 (Cytolab IL).
  • IL-7 recombinant IL-7
  • medium was partial replaced with fresh medium containing 1 ug/ml of ImMucin and 50 IU/ml IL-2 for a third stimulation of 48 h at 37° C. Following the last stimulation ImMucin T cell line was checked for immune activation properties.
  • Cytokine release was studied during the culture of stimulated T-cells.
  • the evaluated samples were collected from the T cell culture medium on day 2, 3, and 5 and stored until use at ⁇ 20° C.
  • the selected capture antibody e.g. anti-Hu IFN-Gamma, or anti-Hu TNF-alfa or anti IL-2
  • the selected capture antibody e.g. anti-Hu IFN-Gamma, or anti-Hu TNF-alfa or anti IL-2
  • a Biotin-conjugated detection antibody (relevant to coated antibody) was added at a final concentration of 10 ⁇ g/ml in total volume of 1000 for 1 h at R.T.
  • 100 ⁇ l/well working dilution (1:10000 in Blocker solution) of Streptavidin-HRP were added to each well and incubated for 1 h at R.T.
  • Proliferation analysis was conducted in three different methods. In all three methods, plates were cultured for 3-5 days under visual control and then 0.5 ⁇ Cu/well of 3[H] (Amersham) was added for additional culture of to 18 h at 37° C. In the last step, plates were harvested and the radioactive counts were measured in a ⁇ counter.
  • Effector cells were ImMucin specific enriched T-Cell clone.
  • Viable lymphocytes effector cells
  • RPMI-HEPES medium RPMI-HEPES medium
  • CTL assays were performed in U-shaped microtiter wells, at 37° C., 5% CO2 for 5 hours. Cultures were terminated by centrifugation at 1000 rpm for 10 min at 40° C. A total of 100 ⁇ l of the supematants was mixed with scintillation fluid and measured in a ⁇ counter (Becton Dickinson Can berra Australia).
  • % lysis (cpm in experimental well ⁇ cpm spontaneous release)/(cpm maximal release ⁇ cpm spontaneous release) ⁇ 100.
  • Spontaneous release was determined by incubation of 100 ⁇ l-labeled target cells with 100 ⁇ l of medium. Maximal release was determined by lysis of target cells in 100 ⁇ l 10% TrytonX-100.
  • PBLs were suspended at a final concentration of 20 ⁇ 10 6 and 50 ⁇ l were transfer into FACS tube (Falcon) in Blocker solution (PBS with 3% FCS and 0.1% Sodium Azide).
  • 10 ⁇ l of fluorochrome-conjugate anti-CD4, anti-CD8, and anti-CD45RO (eBioscience) were added for 30 min on ice at 0° C. in the Dark. After the incubation cell were washed with 2 ml of the blocker solution and re suspended in 0.5 ml of Phosphate buffer saline (PBS). Samples were analyzed in a FACS-sort machine (BD) for positive florescence.
  • BD FACS-sort machine
  • Table 3 describes ImMucin (VLX-100) and other various VXL epitopes used in the experiments.
  • the CTL epitopes VXL1 (D6) and VXL2 (M1.2) were used as positive controls for MUC1's SP and class I epitopes.
  • M1.1 the previously identified CTL epitopes VXL6 (M1.1).
  • VXL-8 the previously identified CTL epitopes derived from the SP domains of other non MUC1 TAA like Her2/neu (VXL-8) or Tyrosinase (VXL-11).
  • As a positive control for class II epitope we used the universal pan-class II epitope peptide PADRE (VXL-14).
  • Proliferation analysis is usually indicating the existence of specific T cells activation mainly CD4 + but could also be associated with CD8 + activation.
  • the most immunogenic antigen is the 21mer ImMucin which manifested a SI, of 4 and 2 respectively for peptide presentation via DC and PBMC (see table 4).
  • SI of ⁇ 2 is considered to be a strong specific activation.
  • the high SI of ImMucin suggests polyclonal T cell activation via binding to multi MHC epitopes. In other words, different epitopes are used in different donors.
  • the index of stimulation for ImMucin's 9mer epitopes was analyzed. Like ImMucin, the class I and/or class II 9mer epitopes VXL-4, VXL-1 and VXL-5 (see Table 4 and 3) manifested high stimulation index of SI>3.
  • SI Index of stimulation
  • a different parameter for assessing the properties of ImMucin and the other VXL-peptide epitopes is by analyzing the time until a maximal peak of activity occurs and the optimal dose for maximal stimulation. Maximal peak of PBL activation is determined when ⁇ 50% of the PBLs appear in clumps. In these experiments, the kinetic (time) in the proliferation of lymphocytes from the six naive donors stimulated at a fix dose of 0.05-1 ug/ml by ImMucin and other VXL-Peptides, was observed.
  • SP-associated sequences/epitopes were noted, e.g. the MUC1 VXL1, 2, and 4 epitopes, but also other SP epitopes such as VXL 8 and VXL11, which contain antigen specific properties for CD4 + and/or CD8 + activation and other sequences (such as VXL-4 and VXL-5) which in addition to CD4 + and/or CD8 + activation also have an “adjuvant like” activity.
  • the adjuvant-like property of signal peptides was already shown in the past by attaching SP to other non-SP epitopes in order to increase their immunity (Sherritt et al., 2001).
  • the relatively slower peak of activity of ImMucin and VXL-1, 2, 6, and 8 can potentially be associated with the time needed for them to enter the APC and move from the Class II compartment into the Class I compartment in a process known as “cross presentation” or “cross priming”. It is known that exogenous antigens can gain entry into the so-called endogenous pathway using the cross-presentation mechanism which is known to be very effective for class I-restricted cytotoxic T lymphocyte (CTL) epitopes.
  • CTL cytotoxic T lymphocyte
  • TNF-Alfa TNF-Alfa
  • IL-2 IFN-gamma
  • TNF-Alfa TNF-Alfa
  • IL-2 IFN-gamma
  • IFN-gamma is produced mainly by CD8 + T cells following IL-2 secretion (late secretion) and is correlates with CD8 + specific activation and function.
  • TNF-Alfa IFN-gamma IL-2 Evaluated antigens IS ng/ml IS ng/ml IS ng/ml ImMucin 4 11.6 4 0.5 4 3.62 VXL-1 3.2 11.1 3.2 0 3.2 0 VXL-2 2.2 0 2.2 0 2.2 0 VXL-4 3.4 17.1 3.4 0 3.4 0 VXL-5 3.74 14.8 3.74 0 3.74 5 VXL-6 1.76 0 1.76 0 1.76 0 VXL-11 1.65 12.8 1.65 0 1.65 0
  • an enriched ImMucin-specific T cell subpopulation was produced via repeated stimulation with ImMucin.
  • the specificity of the subpopulation for ImMucin, as well as to the other VXL epitopes, was examined using proliferation assays, cytokine release assays, FACS analysis in which the percentage and type of cells enriched during the enrichment process was analyzed, and using a CTL assay against selected target cells.
  • PBL For producing the specific T cell subpopulation PBL were stimulated three times for 7, 5 and 2 days with ImMucin presented via DC and PBMC. Following the 3 rd stimulation the cells were evaluated against the different VXL epitopes.
  • each one of the MUC1 SP epitopes VXL1, VXL2, VXL4 and VXL5 induced a specific proliferation with an average IS ranging from 2.66 to 3.5 which was comparable to the SI achieved using ImMucin itself.
  • VXL-11 the SP epitope which is not deduced from the MUC1 antigen and VXL-6 which is a MUC1 epitope which is not deduced form the SP domain manifested lower SI with an average SI of 1.14-1.125 or 2-5 times lower than the MUC1 SP epitopes.
  • the cytokine profile obtained from the specific T cell subpopulation stimulated with the MUC1 SP epitopes VXL1, VXL2, VXL4 and VXL5 conform to the proliferation results, showing again that antigen specificity is positively correlated with cytokine release (Table 9).
  • ImMucin and its SP epitopes VXL1, VXL2, and VXL4 manifested high IL-2 and IFN-gamma secretion compared to low to moderate levels induced by the other epitopes.
  • the secretion of TNF-Alfa which is less specific and appears in an early stage is high in all the epitopes tested.
  • the positive results achieved in this experiment are unique compared with results obtained with class I peptide vaccines since in this experiment ImMucin was not matched with the relevant HLA alleles of the donors and still received a positive proliferation.
  • a breast tumor cell such as MDA-MB-231 which expresses both MUC1 and HLA-A2.1 was lysed effectively (23%), while another breast tumor cell line MDA-MB-468 which expresses only MUC1 but not the HLA-2.1 was not lysed al all.
  • Other control cell-lines didn't manifest any lysis (see table 10).
  • ImMucin is able to induce antigen specific CD4 + as well as CD8 + T cell activation which can lead to effective anti-tumor vaccine properties including lysis, cytokine release and memory in the majority of the population.
  • VXL102 SEQ ID NO. 7
  • VXL101 SEQ ID NO 1
  • ARMET novel protein
  • VXL-102 manifested lower SI than VXL-101 and ImMucin but still higher than the non-SP epitope VLX-6.
  • a similar pattern of results was obtained in ELISA assay analyzing the cytokine profile of the peptide-activated T cells (Table 12). While all peptides induced high secretion levels of TNF-Alfa ( ⁇ 10 ng/ml), only ImMucin induced IL-2 and VXL-101 induced INF-Gamma suggesting that enrichment of CD4+ and CD8+ T cells occurred.
  • VXL-102 didn't induced IL-2 or IFN-gamma production. This moderate immunogenic profile could be associated with the HLA match of the two donors used in this experiment.

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